The Strategic Timing of Antiretroviral Therapy (START) study is a multicontinental randomised study designed to determine the risks and benefits of the immediate initiation of antiretroviral therapy in asymptomatic HIV positive patients who have CD4+ count > 500 cells/mm3 , as compared with deferring initiation until the CD4+ count is 350 cells/mm3 . Eligibility criteria were: HIV positivity, age ≥ 18 years, antiretroviral therapy naïve, no history of AIDS, general good health, two CD4+ counts >500 cells/mm3 at least 2 weeks apart within 60 days before enrollment. Patients were randomly assigned to 2 strategies for initiating antiretroviral therapy: immediate initiation and deferred initiation until the CD4+ count declined to 350 cells/mm3 or the development of an AIDS-related event or another condition that dictated the use of antiretroviral therapy (e.g., pregnancy). The primary composite end point was: serious AIDS-related event (death from AIDS, AIDS-defining event with the exception of nonfatal herpes simplex virus infection and esophageal candidiasis, and addition of Hodgkin's lymphoma) or serious non–AIDS-related event (cardiovascular disease, end-stage renal disease, decompensated liver disease, non–AIDS-defining cancer, and death from cause unrelated to AIDS). For the statistical analysis, the 2 study groups were compared according to the intention-to-treat principle. Time-to-event methods were used, including Kaplan–Meier survival curves and Cox proportional-hazards models, to compare the 2 groups for the primary end point, its 2 major components and death from any cause.
A total of 4,685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651/mm3 . On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval, 0.30 to 0.62; p < 0.001). Hazard ratios for serious AIDS-related and serious non–AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; p < 0.001) and 0.61 (95% CI, 0.38 to 0.97; p = 0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count > 500 cells/mm3 . The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.
In conclusion, the initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count > 500 cells/mm3 provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells/mm3 .
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